Medicinal preparation for dysmenorrhea



Patented June 24, 1952 MEDICINAL PREPARATION FOR DYSIMENORRHEA John Henderson, Princeton, N. J., assignor to a Johnson & Johnson, a corporation of New Jersey No Drawing. Application December 20, 1949, Serial No. 134,142

8 Claims. (Cl. 167-55) This invention relates to pharmaceuticals and is particularly concerned with medical preparations for the relief of primary dysmenorrhea. The application is a continuation in part of application Ser. No. 767,355, filed August '7, 1947, now abandoned, by the same inventor.

Primary dysmenorrhea is a condition present in physically perfectly normal women, even in the absence of any organic disease. To many women it manifests itself during menstruation as sharp, intermittent cramps centering usually in the lower abdomen, but frequently radiating towards various other parts and organs of the body. These cramps are accompanied by varying degrees of premenstrual tension, headaches and nervousness, all of which are part of the clinical picture of primary dysmenorrhea. Primary dysmenorrhea is distinguished from secondary dysmenorrhea which occurs as a result of abnormal conditions such as pelvic lesions, inflammatory diseases, tumors, or emotional or physical strain.

In view of the large number of otherwise healthy women who are subject to primary dysmenorrhea, this affliction has undergone considerable study, many attempts having been made to improve the well-being of patients suffering from the condition. Most of the eiforts to find a remedy have centered around the use of so-called pain killers." Such preparations are based on one or another standard type of sedative or analgesic or a combination thereof. These preparations tend to relieve milder cases of primary dysmenorrhea by blocking sensory perception of the pain or of the discomfort caused by the underlying pathology of uterine spasm and congestion. They have no specific action that would relieve or cqunteract this condition. Accordingly, designation of such analgesics or sedatives as drugs for the specific relief of functional dysmenorrhea is not approved by government authorities.

Prior to .the invention, efforts to provide specific relief against primary dysmenorrhea were largely unsuccessful, due mainly to the fact that those prior agents which would relieve this condition were so strong as to endanger the health of the user, particularly if such drugs were taken freely and without the guidance of a physician. Frequently the deleterious effects upon general health would outweight the small amount of relief from primary dysmenorrhea that such agents could offer.

The product of this invention has a specific action for the relief of primary dysmenorrhea and of conditions associated therewith. Several types of the new product may be used safely without prescription. Safe doses provide substantial relief. Scientific experiments establishing the efficiency of the product of the invention show conclusively that its use results in the complete or partial relief of primary dysmenorrhea in almost every case. In the few instances where pains persist after treatment with the product of the invention, secondary dismenorrhea or possibly nervousness or allergies are probably to blame.

The invention is based upon the surprising discovery that theophylline compounds have a strong action upon the uterine spasm and congestion of primary dysmenorrhea even when such compounds are administered in relatively minor amounts and that this action is substan tially enhanced by addition to the theophylline compounds, of iron compounds, preferably of the ferrous type. In animal experiments it was noted that menstrual cramps would subside shortly after administration of theophylline compounds. Similar phenomena were observed in the treatment of human dysmenorrhea using synergistic preparations of iron compounds and theophylline compounds as indicated below.

Whenever in this specification mention is made of a theophylline compound, the intention is to include in this term the broad group of therapeutic theophylline compounds, salts and mixtures thereof including specifically but not exclusively theophylline, theophylline calcium salicylate, theophylline diethanolamine, theophylline ethylenediamine, theophylline sodium acetate and theophylline sodium salicylate.

The iron in the composition may be supplied through any of the many well known non-toxic compounds providing available iron. Among the preferred ferrous compounds are ferrous sulfate, ferrous iodide, ferrous phosphate, ferrous carbonate, ferrous lactate, Saccharated Ferrous Carbonate, N. F., ferrous gluconate, ferrous sodium pyrophosphate, ferrous ammonium pyrophosphate, and ferrous ammonium sulfate. Other available iron compounds that may be used, although with somewhat less activating effect for the theophylline compound are iron and ammonium citrate, iron and ammonium tartrate, ferric glycerophosphate, ferric hypopho'sphite, yellow iron oxide, red iron oxide, Saccharated Ferric Oxide, N. F., Soluble Ferric Pyprophosphate, N. F., Soluble Ferric Phosphate, N. F. Citrated Ferric Chloride (Bt. Addn. 1), iron peptonate, reduced iron, ferric albuminate, ferric ammonium sulfate, ferric potassium tartrate, and basic ferric sulfate.

The above composition alone, while essential to the treatment, does not give all the desired relief apparently because it lacks analgesic properties to some extent. Accordingly, the product of the invention preferably comprises a combination of a theophylline with a mildly analgesic preparation. In other words, the addition of mild analgesic (for instance acetylsalicylic acid, acetophenetidin and/or acetanilid) is desirable for complete relief. In addition, in the preferred embodiments of the invention, a mildly ,analeptic substance such as caffeine or amphetamine sulfate is desirably added. The analeptic assists in relieving the mental stress of those suffering from dysmenorrhea.

Other auxiliary ingredients may prove advantageous in compounding some oi the formulae which are within the scope of the invention. Thus stabilizers for the theophylline compound maybe added, for example, the buffering phosphates such as dibasio or monobasic sodium phosphate or calcium phosphate, sodium citrate, potassium citrate, sodium tartrate, potassium tartrate, or sodium acid tartrate. Inert fillers or lubricants may also be added to furnish bulk or to assist in the compounding of the preparation.

The daily requirements of theophylline compound will vary within limits depending upon the particular compound used, the specific treatment and the use. The dailyneedof mild anal-- gesic in connection with the preparation will depend largely upon the specific type of analgesic used. Theproportionsar-e compounded in weight relations so as to provide standard daily dosages of the analgesic, as defined for each analgesic in the'U. S. Pharmacopeia along with the suggested dosage of the theophylline compound.

Using :standard mild analgesics i-n .inost cases thewe'ight relation :of the theophylline compound to the analgesic in the preparation will be between ifs-parts .and 1122 parts. Those skilled theart will readily understand that the higher ratios are 10f greater value if the theophylline compound'used is of the more active type and the analgesic .rather weak in action, while the lower ratios are desirable it relatively weak theophylline compounds and strong analgesics are present in'the compositions.

If a stabilizer-is utilized, the amount is preferably :a small'lfraction of the amount of theophylline compoundrpresent. The iron compound is utilized preferably in an amount by weight of available iron :be'tween one-tenth the weight of the theophylline compound and one and onehalf its weight although a larger excess of iron in the composition is not harmful. Usually not less than one-quarter of apart and not more than three parts of mild analeptic is present per part of the theophylline compound.

Fillers such :as starch, magnesium oxide, magnesium carbonate or talcum; additional lubricants such as calcium stearate, magnesium stearate or stearicacid; and any other standard additional compounds may be incorporated in the compositions.

In order to illustrate various embodiments of the invention, :several examples in the form of representative formulations are :given in the following table. .It is to be clearly understood, howeyerg'that this is done solely by way of example, and is not to be construed as a limitation upon the spirit .and scope of the present invention, which hasmany important embodiments .Analeptic Ingredients:

4, other than those hereinafter particularly described.

Table Weight In Grain Per Tablet Example 3 ple 5 Example 2 Example 1 Example 4 Analgesic Ingredients:

Acetophenetidin 2 Acetylsalicylic Acid. 2 Aminopyrine Amphetamine Sulfate. Oafieine Caffeine Citrate... 3.7 Dimethylxanthine- Theophylline Compounds:

'Iheophylline l Theophylline Calcium Salicylate. Theophylline Diethanolamine. Theopl ylline Ethylenediamine. Additional Ingredients:

Calcium Stoarate Ferrous Gluconate. Ferrous Sulfate, Anhydrous. Iron, Reduced Sodium Iron ,Pyrophosphate. Sodium Phosphate, Monobasic.

Starch Stearic Acid"-..

[alcum Magnesium Stearate. M

It will be observed that in Example 1, which is a preferred example, the ratio of acetophenetidin to acetylsalicylic acid, bothof which are analgesic ingredients, to an analeptic ingredient (e. g. caffeine) to the theophylline compounds to, the iron compounds is four to four .to one to one to one (as sodium iron pyrophosphate :comprises approximately onethird available iron).

Compositions comprising theophylline ethylenediamine which is also known as aminophylline are preferred because of the greater degree of antispasmodic action on the uterine musculature of this compound as compared with the other theophylline compounds.

By way of example only, a typical method for the preparation of the product of Example 1 is as follows: The theophylline compound, the stabilizer (if any), the acetophenetidin and the analeptic, together with half the iron compound are intimately mixed andthereafter sieved. The sieved mixture is Wetted 'or granulated with a ten per cent starch paste to :bring the mixture *to'the proper consistency. The mixture is passed through .a screen to form granules of any desired small size, and dried thoroughly at approximately .120 F. Meanwhile, one-half of the iron compound, all the .acetylsalicylic and addi- These tablets may comprise for example 0.2-3

grains of the theophylline compound and corresponding amounts of the other materials in accordance with this specification.

The value of the newpreparation .has been "fully established. Using the product of the invention, 84.1 per cent of the subjects tested under supervision of leading medical experts reported complete relief, while with some of the best available preparations of the prior art it has been impossible to give complete relief in more than seventeen per cent of the cases tested. In absence of the available iron compound only 51.2 per cent of the subjects tested reported complete relief. The test with the product of the invention was conducted on nine hundred subjects, the preparation using a theophylline compound without available iron was tested on one hundred twenty-three subjects, and the preparation of the prior art was tested on ninety-eight subjects. Statistical analysis proved the results to be reproduceable. Those tested were selected at random from sufferers from primary dysmenorrhea who had been disabled by the condition. Those reporting complete relief were able to return to their regular occupations within a short time after treatment, while the others either had to leave their place of employment for home, or withdraw from work for periods of several hours.

All embodiments within the scope of this specification and/or the appended claims are comprehended in the invention. Various embodiments of the invention were described for purposes oi illustration rather than of limitation.

What is claimed is as follows:

1. A composition comprising theophylline ethylenediamine, caffeine, acetylsalicylic acid, acetophenetidin, sodium iron pyrophosphate, and monobasic sodium phosphate, said composition comprising substantially four parts by weight each of acetylsalicylic acid and acetophenetidin per part of theophylline ethylenediamine.

2; A composition comprising about one part by weight of theophylline compound, from about one-quarter of a part to about three parts of mild analeptic, from about three to about twenty- 5 two parts of analgesic, and ferrous iron compound comprising from about one-tenth to about one and one-half parts by weight of available iron.

3. A composition comprising about one part by weight of theophylline compound, from about one-quarter of a part to about three parts of mild analeptic comprising caffeine zfrom about three to about twenty-two parts of analgesic, and iron compound comprising from about onetenth to about one and one-half parts by weight of available iron.

4. A composition comprising about one part by weight of analgesic compound, from about one-quarter of a part to about three parts of mild analeptic, from about three to about twenty-two parts of analgesic comprising acetylsalicylic acid, and iron compound comprising from about one-tenth to about one and onehalf parts by weight of available iron.

5. A composition comprising about one part by weight of theophylline compound, from about one-quarter of a part to about three parts of mild analeptic, from about three to about twenty-two parts of analgesic, and iron compound comprising from about one-tenth to about one and one-half parts by weight of available iron.

6. A product according to claim 2 wherein the theophylline compound is acetophenetidin.

7. A product according to claim 2 wherein the theophylline compound is theophylline ethylenediamine.

8. A product according to claim 2 containing a buffering stabilizer for the theophylline compound.

JOHN HENDERSON.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Andersen Nov. 5, 1946 OTHER REFERENCES Number 

5. A COMPOSITION COMPRISING ABOUT ONE PART BY WEIGHT OF THEOPHYLLINE COMPOUND, FROM ABOUT ONE-QUARTER OF A PART TO ABOUT THREE PARTS OF MILD ANALEPTIC, FROM ABOUT THREE TO ABOUT TWENTY-TWO PARTS OF ANALGESIC, AND IRON COMPOUND COMPRISING FROM ABOUT ONE-TENTH TO ABOUT ONE AND ONE-HALF PARTS BY WEIGHT OF AVAILABLE IRON. 